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Category: The Microbiome

The Microbiome and Clostridium difficile

Sabine Hazan, MD Daniel Frochtzwajg, DO Jessica Murray, BS Ventura Clinical Trials, Ventura, CA

INTRODUCTION

Cdifficile is a gram-positive, spore forming bacillus that is an obligate anaerobe and has been identified as one of the most common causes of nosocomial infection in the developed world, causing mild to severe cases of diarrheal illness to life-threatening pseudomembranous colitis and toxic megacolon,3 with increasing incidence over the last decade.2,4 C. difficile infection (CDI) risk factors include extended hospital stay, protracted antibiotic regimens, other illnesses and comorbidities, and age greater than 65 years.1 In addition to the logistic complications of identifying, diagnosing, and containing infections in a hospital, and even community setting, there is substantial cost incurred as a result of CDI and the high risk of recurrent infection. In The Economic Impact of Clostridium difficile Infection: A Systemic Review, Nanwa et al. analyzed 45 cost-of-illness (COI) studies and determined that, for hospitalized patients, CDI costs range from $8,911 to $30,049.11 For decades, the standard treatment of CDI included antibiotic therapy with either metronidazole or vancomycin, however, even with the development of tapered or pulsed antibiotic regimens demonstrating improvement in recurrence rates, still some 14-31% of patients would experience repeat bouts of CDI.10 Furthermore, the risk of recurrent infection increases with every subsequent infection and by the third episode, rates become greater than 50%.4,10 Despite medical professionals’ increased awareness of the burden of CDI, there is still no consensus on treatment regimens and no standardized optimal approach to treating recurrent CDI exists.

The solution to the worsening burden of CDI may exist in the intestinal microbiome. There is already substantial evidence that fecal microbiota transplantation (FMT), the implantation of either a patient’s own stool (autologous transplant) or healthy donor stool (heterologous transplant) into a patient with gut dysbiosis caused by CDI, is a preferable alternative to traditional antibiotic therapy.7 A 2013 review and meta-analysis in the American Journal of Gastroenterology demonstrated that FMT resulted in resolution of infection in nearly 90% of patients affected by recurrent CDI.6,9 To reiterate the ideas addressed in our introduction, the suggestion of a mechanism of action is the restoration of the healthy composition of an individual’s intestinal microbiome. In addition to its efficacy, FMT presents an almost adverse event free means of cure. While some adverse events, including fever, abdominal pain, bloating, nausea, vomiting, diarrhea, flatulence, anorexia, and constipation have been reported after FMT, there have been no severe adverse events and no death attributable to FMT alone.8 Earlier research suggested that lower gastrointestinal FMT delivery resulted in high rates of clinical resolution than oral capsular implantation.6 However, in a very recent randomized controlled trial by Kao et al published in the November 2017 issue of JAMA, rates of minor adverse events were as low as 5.4%.5 In the same study, Dr. Kao demonstrates the noninferiority of oral capsule FMT to colonoscopy-delivered FMT, an important finding given that the colonoscopic method was reported as less pleasant than the capsule.5 Not only are delivery methods for FMT being refined, but models for the risk of FMT failure in the treatment of CDI have been developed. In Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium difficile Infection: A Multicenter Study published in the American Journal of Gastroenterology, Fischer et al. define risk score based on severity of CDI, number of CDI-related hospitalizations prior to FMT, and inpatient status.4 Although standard algorithm for the use of FMT as a treatment for recurrent CDI does not yet exist, this risk calculator will help to guide physicians as the use of FMT is pioneered.

The microbiome and its associations with disease states, and hence its potential to offer insight into new cures is in a fledgling state.

References

1. Badger, V.O., et al. “Clostridium difficile: epidemiology, pathogenesis, management, and prevention of a recalcitrant healthcare-associated pathogen.” Journal of Parenteral and Enteral Nutrition, vol 36, no. 6, 2012, pp. 645-62., doi:10.1177/0148607112446703.
2. Bartlett, J.G., et al. “Historical perspectives on studies of Clostridium difficile and C. difficile infection.” Clinical Journal of Infectious Disease, vol 46, supplement 1, 2008, pp. S4-11., doi:10.1086/521865.
3. Bomers, Marije, et al. “Rapid, Accurate, and On-Site Detection of C. difficile in Stool Samples.” American Journal of Gastroenterology, vol 110, no. 4, 2015, pp. 588-94., doi:10.1038/ajg.2015.90.
4. Fischer, Monika, et al. “Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study.” American Journal of Gastroenterology, vol 111, no. 7, 2016, pp. 1024-31., doi:10.1038/ajg.2016.180.
5. Kao, Diana, et al. “Effect of Oral Capsule-vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection, A Randomized Clinical Trial.” Journal of the American Medical Association, vol 318, no. 20, 2017, pp. 1985-93., doi:10.1001/jama.2017.17077.
6. Kassam, Z., et al. “Fecal Microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.” American Journal of Gastroenterology, vol 108, no. 4, 2013, pp. 500-8., doi:10.1038/ajg.2013.59.
7. Kelly, Colleen, et al. “Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection.: Annals of Internal Medicine, vol 165, no. 9, 2016, pp. 609-16., oi:10.7326/M16-0271.
8. Li, Junhua, et al. “An integrated catalog of reference genes in the human gut microbiome.” Nature Biotechnology, vol 32, no. 8, 2014, pp. 834-41., doi:10.1038/nbt.2942.
9. Mattila, E, et al. “Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile Infection.” Gastroenterology, vol 142, no. 3, 2012, pp. 490-6., doi:10.1053/j.gastro.2011.11.037.
10. McFarland, Lynne V., et al. “Breaking the Cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile Disease.” American Journal of Gastroenterology, vol 97, no. 7, 2002, pp. 1769-75., doi:10.1111/j.1572-0241.2002.05839.x.
11. Nanwa, Natasha, et al. “The Economic Impact of Clostridium difficile Infection: A Systematic Review.” American Journsal of Gastroenterology, vol 110, no. 4, 2015, pp. 511-519., doi:10.1038/ajg.2015.48.
The Microbiome and Clostridium difficile

Sabine Hazan

Daniel Frochtzwajg

Jessica Murray

The Microbiome and Inflammatory Bowel Disease

The Microbiome and Inflammatory Bowel Disease
The Microbiome and Inflammatory Bowel Disease

Sabine Hazan Steinberg

Daniel Frochtzwajg

Jessica Murray

Sabine Hazan Steinberg MD, Gastroenterology/Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center Dr. Daniel Frochtzwajg DO, Research Assistant, Ventura Clinical Trials Jessica Murray BS, Research Assistant, Ventura Clinical Trials, Ventura, CA

Ulcerative colitis (UC) and Crohn’s disease are the two chronic and progressive inflammatory states that commonly define inflammatory bowel disease (IBD). UC is typically characterized by continuous mucosal inflammation that involves that rectum and colon and often presents as bloody diarrhea. In Crohn’s disease, inflammation is spotty, transmural and can be observed in any portion of the gastrointestinal tract. IBD affects roughly 1.4 million people in the United States and some 2.2 million in Europe.5,6 The steadily increasing incidence and prevalence of IBD, as well as the association of IBD and urban living, suggests that environment plays a critical role in the development of these diseases.8,13 This hypothesis, in conjunction with the documented variations in gut microbiome associated with industrialization and geography,3 has led researchers to pursue the intestinal microbiota as an avenue for diagnostic and therapeutic intervention.

It is thought that a shift in composition of the intestinal microbiome may contribute to the development of IBD in genetically susceptible individuals. Initially hinted at by studies demonstrating such things as a reduced risk of IBD in breastfed infants or increased risk in those with low vitamin D levels,1,2,10 the new age of bioinformatics has enabled corroboration of this theory. One example of the complex genetic-microbe interplay is a study by Ijaz et al.. demonstrating that adult relatives of patients with Crohn’s disease had less diverse intestinal microbiota than healthy adults unrelated to IBD patients.4

While there is no singular microbe responsible for IBD, gut dysbiosis is clearly implicated.5 An overall reduction in microbial diversity has been observed as well as specific, relative increases and decreases in “good” and “bad” microbes.5,9,12 In Sartor and Wu’s extensive 2017 review, Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Disease and Therapeutic Approaches, the authors distill the latest documented genetic compositional changes in the intestinal microbiome of IBD patients.12 They identify the overarching theme of the associated dysbiosis as a decrease in known “protective” bacteria such as Bifidobacterium species and an expansion of potentially inflammatory microbes like Proteobacteria, Fusobacterium species, and invasive E. coli.12

The common treatments for UC and Crohn’s, including immunosuppressive therapies, mesalamine, glucocorticoids, and tumor necrosis factor antagonists, rarely induce remission and colectomy is too often an undesirable endpoint. Furthermore, an IBD patient’s quality of life can be significantly diminished when treated with conventional therapies.17 However, like the trend of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection, there is promising evidence that a similar approach will prove efficacious in treating UC and Crohn’s, especially given the increasingly predictable intestinal microbiome perturbation. In one of the premier studies of alternative treatments for IBD, Moayyedi et al. demonstrate, in a randomized controlled trial, that FMT can induce remission in UC patients.7 Researchers used the Mayo score for UC, which includes scores for stool pattern, rectal bleeding, endoscopic findings, and physician assessment (scores ranges from 0-12, with higher scores correlating with increased disease severity) to assess patients. Eligible enrollees were adults 18 years or older with active UC determined by a Mayo score ≥4 (with an endoscopic score ≥1); remission was defined as a Mayo score <3 at seven weeks. FMT from healthy donors was completed via retention enemas administered once weekly for six weeks. Overall, 9 of the 38 patients in the FMT treatment arm achieved remission, compared to 2 of the 37 patients in the placebo arm. Moreover, there was no difference in serious adverse events between the two groups. In another promising prospective, uncontrolled study, by Uygun et al. response of UC patients to FMT was examined.14 Responders were defined as a decrease in Mayo score ≥30%. 21 patients in the study, 70% of the subjects, were ultimately classified as responders. While 9 patients were categorized as non-responders, there was still improvement in CRP and hemoglobin levels after FMT.

Despite the positive findings mentioned above, there is conflicting data, and in another RCT, Rossen et al.11 did not demonstrate a difference in the remission rate of FMT vs. placebo. However, increased intestinal microbiome richness following FMT has been shown in patients with Crohn’s, and there is evidence to suggest that FMT donor species richness determines efficacy of FMT treatment for IBD.15,16

Ultimately, while current data is cause for optimism, more foundational research is necessary to characterize the microbe-gene interaction and define a treatment paradigm.

 

 

References

1. Ananthakrishnan, A.N., et al. “Higher predicted vitamin D status is associated with reduced risk of Crohn’s disease.” Gastroenterology, vol 142, no. 3, 2012, pp. 482-89., doi: 10.1053/j.gastro.2011.11.040.
2. Barclay, A.R., et al. “Systematic review: the role of breastfeeding in the development of pediatric inflammatory bowel disease.” Journal of Pediatrics, vol 155, no. 3, 2009, pp. 421-6., doi: 10.1016/j.jpeds.2009.03.017.
3. Gupta, Vinod K., et al. “Geography, Ethnicity or Subsistence-Specific Variations in Human Microbiome Composition and Diversity.” Frontiers in Microbiology, vol 8, no. 1162, 2017., doi: 10.3389/fmicb.2017.01162.
4. Ijaz, Umer Zeeshan, et al. “The distinct features of microbial ‘dysbiosis’ of Crohn’s disease do not occur to the same extent in their unaffected, geneticallylinked kindred.” PLoS ONE, vol 12, no. 2, 2017., doi: 10.137/journal.pone.0172605.
5. Lane, Erin R., et al. “The microbiota in inflammatory bowel disease: current and therapeutic insights.” Journal of Inflammation Research, vol 10, 2017, pp. 63-73., doi:10.2147/JIR.S116088.
6. Loftus, E.V. Jr. “Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology, vol 126, no. 6, 2004, pp. 1504-1517., doi: 10.1053/j.gastro.2004.01.063.
7. Moayyedi, Paul, et al. “Fecal Microbiota Transplantation Induces Remission in Patients with Active Ulcerative Colitis in a Randomized Controlled Trial.” Gastroenterology, vol 149, no. 1, 2015, pp. 102-109., doi: 10.1053/j.gastro.2015.04.001.
8. Molodecky, N.A., et al. “Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.” Gastroenterology, vol 142, no. 1, 2012, pp. 46-54., doi: 10.1053/j.gastro.2011.10.001.
9. Morgan, X.C., et al. “Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.” Genome Biology, vol 13, no. 9, R79, 2012., doi: 10.1186/gb-2012-13-9-r79.
10. Penders, J., et al. “Factors influencing the composition of the intestinal microbiota in early infancy.” Pediatrics, vol 118, no. 2, 2006, pp. 511-521., doi: 10.1542/peds.2005-2824.
11. Rossen, N.G., et al. “Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis.” Gastroenterology, vol. 149, 2015, pp. 110-118., doi: 10.1053/j.gastro.2015.03.045.
12. Sartor, R. Balfour, and Gary D. Wu. “Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.” Gastroenterology, vol 152, no. 2, pp. 327-339., doi: 10.1053/j.gastro.2016.10.012.
13. Soon, Ing Shian, et al. “The relationship between urban environment and the inflammatory bowel diseases: a systematic review and meta-analysis.” BMC Gastroenterology, vol 12, no. 51, 2012., doi: 10.1186/1471-230X-12-51.
14. Uygen, Ahmet, et al. “Fecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis.” Medicine, vol 96, no. 16, 2017., doi: 10.1097/MD.0000000000006479.
15. Vaughn, Byron P., et al. “Increased Intestinal Microbial Diversity following Fecal Microbiota Transplant for Active Crohn’s Disease.” Inflammatory Bowel Disease, vol 22, no. 9, 2016, pp. 2182-90., doi: 10.1097/MIB.0000000000000893.
16. Vermeire, Severine, et al. “Donor Species Richness Determines Faecal Microbiota Transplantation Success in Inflammatory Bowel Disease.” Journal of Crohn’s and Colitis, vol 10, no. 4, 2016, pp. 387-394., doi: 10.1093/ecco-jcc/jjv203.
17. Wei, Yao, et al. “Fecal Microbiota Transplantation Improves the Quality of Life in Patients with Inflammatory Bowel Disease.” Gastroenterology Research and Practice, vol 2015, 2015., doi: 10.1155/2015/517597.